👤 Majumdar P

Fourteen new Ru^II -arene (p-cymene/benzene) complexes (C1-C14) have been synthesized by varying the N-terminal substituent in the furoylthiourea ligand and satisfactorily characterized by using analytical and spectroscopic techniques. Electrostatic potential maps predicted that the electronic effect of the substituents was mostly localized, with some influence seen on the labile chloride ligands. The structure-activity relationships of the Ru-p-cymene and Ru-benzene complexes showed opposite trends. All the complexes were found to be highly toxic towards IMR-32 cancer cells, with C5 (Ru-p-cymene complex containing C₆ H₂ (CH₃ )₃ as N-terminal substituent) and C13 (Ru-benzene complex containing C₆ H₄ (CF₃ ) as N-terminal substituent) showing the highest activity among each set of complexes, and hence they were chosen for further study. These complexes showed different behavior in aqueous solutions, and were also found to catalytically oxidize glutathione. They also promoted cell death by apoptosis and cell cycle arrest. Furthermore, the complexes showed good binding ability with the receptors Pim-1 kinase and vascular endothelial growth factor receptor 2, commonly overexpressed in cancer cells. Show less

Drug resistance to existing anticancer agents is a growing clinical concern, with many first line treatments showing poor efficacy in treatment plans of some cancers. Resistance to platinum agents, such as cisplatin, is particularly prevalent in the treatment of ovarian cancer, one of the most common cancers amongst women in the developing world. Therefore, there is an urgent need to develop next generation of anticancer agents which can overcome resistance to existing therapies. We report a new series of organoruthenium(II) complexes bearing structurally modified pyrithione ligands with extended aromatic scaffold, which overcome platinum and adriamycin resistance in human ovarian cancer cells. The mechanism of action of such complexes appears to be unique from that of cisplatin, involving G₁ cell cycle arrest without generation of cellular ROS, as is typically associated with similar ruthenium complexes. The complexes inhibit the enzyme thioredoxin reductase (TrxR) in a model system and reduce cell motility towards wound healing. Importantly, this work highlights further development in our understanding of the multi-targeting mechanism of action exhibited by transition metal complexes. Show less

Antibiotic resistance is a global problem, and one promising solution to overcome this issue is using metallodrugs, which are drugs containing metal ions and ligands. These complexes are superior to free ligands in various characteristics including anticancer properties and mechanism of action. The pharmacological potential of metallodrugs can be modulated by the appropriate selection of ligands and metal ions. A good example of proper coordination is the combination of sulfonamides (sulfamerazine, sulfathiazole) with a ruthenium(III) ion. This work aimed to confirm that the activity of sulfonamides antibacterial drugs is initiated and/or stimulated by their coordination to an Ru(III) ion. The study determined the structure, electrochemical profile, CT-DNA affinity, and antimicrobial as well as anticancer properties of the synthesized complexes. The results proved that Ru(III) complexes exhibited better biological properties than the free ligands. Show less

Four photo-catalysts of the general formula [Ir(CO6/ppy)₂ (L)]Cl where CO6=coumarin 6 (Ir1-Ir3), ppy=2-phenylpyridine (Ir4), L=4'-(3,5-di-tert-butylphenyl)-2,2' : 6',2''-terpyridine (Ir1), 4'-(3,5-bis(trifluoromethyl)phenyl)-2,2' : 6',2''-terpyridine (Ir2 and Ir4), and 4-([2,2' : 6',2''-terpyridin]-4'-yl)-N,N-dimethylaniline (Ir3) were synthesized and characterized. These photostable photo-catalysts (Ir1-Ir3) showed strong visible light absorption between 400-550 nm. Upon light irradiation (465 and 525 nm), Ir1-Ir3 generated singlet oxygen and induced rapidly photo-catalytic oxidation of cellular coenzymes NAD(P)H. Ir1-Ir3 showed time-dependent cellular uptake with excellent intracellular retention efficiency. Upon green light irradiation (525 nm), Ir2 provided a much higher photo-index (PI=793) than the clinically used photosensitizer, 5-aminolevulinicacid (5-ALA, PI>30) against HeLa cancer cells. The observed necro-apoptotic anticancer activity of Ir2 was due to the Ir2 triggered photo-induced intracellular redox imbalance (by NAD(P)H oxidation and ROS generation) and change in the mitochondrial membrane potential. Remarkably, Ir2 showed in vivo photo-induced catalytic anticancer activity in mouse models. Show less

Glioblastomas (GBs) are highly aggressive and malignant brain tumors, which are highly resistant to conventional multimodal treatments, leading to their abysmal prognosis. Herein, we designed two organometallic half-sandwich Ru(ii)-η6-p-cymene complexes containing Schiff bases derived from 3-aminoquinoline and 2-hydroxy-benzaldehyde (L1) and 2-hydroxy-naphthaldehyde (L2), namely [Ru(η6-p-cymene)(L1)Cl] (1) and [Ru(η6-p-cymene)(L2)Cl] (2), respectively, and studied their activity on GB cells. Both complexes were structurally characterized using single-crystal X-ray diffraction, which exhibited their half-sandwich three-legged piano-stool geometry. Furthermore, we studied their physicochemical behavior, solution speciation, aquation kinetics, and photo-substitution reactions using various spectroscopic methods. The complexes exhibited a moderate binding affinity with calf-thymus (CT)-DNA (Kb ∼ 105 M-1). The complexes effectively interacted with human serum albumin (HSA) (K ∼ 105 M-1) with preferential tryptophan binding, as determined via synchronous fluorescence studies. The in vitro studies showed their significant antiproliferative activity against an aggressive human GB cell line, LN-229 (IC50 = 22.8 μM), with moderate selectivity relative to normal mouse fibroblast L929 cells. Notably, [Ru(η6-p-cymene)(L1)Cl] (1) exhibited a higher selectivity index (S.I.) than [Ru(η6-p-cymene)(L2)Cl] (2) and cisplatin. We evaluated the clonogenic potential of the GB cells using a colony formation assay in the presence of complex 1. Excitingly, it showed ∼75% inhibition of the clonogenic potential of GB cells at the IC50 concentration. Complex 1 also effectively lowered the migratory potential of the GB cells, as assessed by the wound healing assay. The studied compound led to the apoptosis of GB cells, as evidenced by nuclear condensation, blebbing, and enhanced caspase 3/7 activity, and thus has anticipated utility in the treatment of GBs using photochemotherapy. Show less

Three new ruthenium(II)-arene complexes, [Ru(η⁶-p-cymene)(L¹)Cl₂] (C1) where L¹ is N-((4 methoxyphenyl)carbamothioyl)benzamide; [Ru(η⁶-p-cymene)(L²)Cl₂] (C2) where L² is 4-(3-benzoylthioureido)benzoic acid and [Ru(η⁶-p-cymene)(L³)Cl₂] (C3) where L³ is methyl 4-(3- benzoylthioureido)benzoate have been synthetized, characterized and evaluated for their antimicrobial and anticancer activity. Characterization was performed using ¹H and ¹³C NMR, IR spectroscopy, mass spectrometry, electrical conductivity measurements and X-Ray diffraction analysis. X-Ray diffraction analysis of C1 showed typical expected "piano-stool" geometry with ruthenium coordinated to ligand via nitrogen and sulfur atoms of benzoylthiourea derivatives. Interesting, in herein described complex, upon coordination the four-membered ring was formed, instead of six-membered chelate common for this type of ligands. Cytotoxic activity was determined in human cervix adenocarcinoma (HeLa) cell line and IC₅₀ values ranged from 29.68 to 52.36 μM and the complexes were more active than related ligands (except in case of C2 where it is found that IC₅₀ value is close to IC₅₀ value of related ligand). Complex [Ru(η⁶-p-cymene)(L¹)Cl₂] (C1) expressed the highest cytotoxic activity with IC₅₀ value of 29.7 μM. Complexes and ligands were tested against nine Gram-positive and Gram-negative bacteria and one yeast- Candida albicans. Clinical Candida spp. strains from microbiological laboratories were included in testing processes as well. Minimum inhibitory concentrations values ranged from 62.5 μg/ml for complexes against Candida albicans to over 1000 μg/ml for several bacterial species. Show less

Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a search for new chemotherapeutic drugs. Many classes of compounds have been investigated over the years to discover new targets and synergistic mechanisms of action including multicellular targets. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely, [Ru(DIP)₂(sq)](PF₆) (Ru-sq) (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated with the catecholate moiety. Experimental evidence (e.g., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrates that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of Ru-sq was then scrutinized in vitro and in vivo, and the results highlight the promising potential of this complex as a chemotherapeutic agent against cancer. Show less

The effective design of metal complexes to manipulate their lipid-water distribution coefficient is an appealing strategy for improving their cellular penetration and treatment efficacy. Here, we conveniently synthesized three iridium (Ir) complexes with red fluorescence via the simple non-conjugate modification of the side arm of the ligand. Bio-evaluation revealed that upon adding non-conjugate selenium (Se) arene derivatives, the lipid-water distribution coefficient of Ir-Se was found to be suitable, not only decreasing the toxic side effects of complexes to normal cells, but also effectively improving their anticancer activity via enhancing their penetration into tumor cells. Moreover, mechanistic investigations demonstrated that Ir-Se entered R-HeLa cells through endocytosis, and triggered apoptosis via the down-regulation of the mitochondrial membrane potential and excessive production of singlet oxygen, thereby possessing a highly effective cytotoxicity to antagonize cisplatin resistance. Therefore, we developed a convenient strategy to derive functional metal complexes and revealed that the introduction of Se on the side arm of the ligand provided the complexes with the capacity to reverse multidrug resistance. Show less

Half-sandwich Cp*-Rh complexes containing curcuminoids ([Rh(η⁵-Cp*)(L)(Py)]PF₆, 1-3, L = curcuminoid ligands L¹-L³) were prepared, characterized and studied for anticancer activity. Complex 1 was structurally characterized by single-crystal X-ray crystallography. Complex 3 presented excellent photodynamic anticancer effect in light (>400 nm) showing IC₅₀ values of 7.5 and 4.3 μM against HepG2, SKOV3 and HeLa, respectively, along with the 12.4, 7.9 and 4.7-fold lower toxicity in the dark. Confocal fluorescence images show that the complex primarily targeted mitochondrial localization. These results suggest that the complex 3 was a valuable agent with higher efficacy for chemotherapy and photodynamic therapy, which can achieve real-time image guidance in cancer therapy for the fluorescence of the complex as imaging signals. This investigation provides a valuable route to design novel half-sandwich Cp*-Rh complexes with higher efficacy for photodynamic anticancer chemotherapy. Show less

The ruthenium(II) complexes [RuCl(L¹)(L³)]Cl (1), [RuCl(L¹)(L⁴)]Cl (2), [RuCl(L²)(L⁴)]Cl (3), [RuCl(L¹)(L⁵)]Cl (4), and [RuCl(L²)(L⁵)]Cl (5) of NNN-donor dipicolylamine (dpa) bases (L⁴, L⁵) having BODIPY (boron-dipyrromethene) moieties, NN-donor phenanthroline derivatives (L¹, L²), and benzyldipicolylamine (bzdpa, L³) were prepared and characterized by spectroscopic techniques and their cellular localization/uptake and photocytotoxicity studied. Complex 1, as its PF₆ salt (1a), has been structurally characterized with help of a single-crystal X-ray diffraction technique. It has a RuN₅Cl core with the Cl bonded trans to the amine nitrogen atom of bzdpa. The complexes showed intense absorption spectral bands near 500 nm (ε ≈ 58000 M^-1 cm^-1) in 2 and 3 and 654 nm (ε ≈ 80000 M^-1 cm^-1) in 4 and 5 in 1/1 DMSO/DPBS (v/v). Complex 5 having biotin and PEGylated-disteryl BODIPY gave a singlet oxygen quantum yield (Φ_Δ) of ∼0.65 in DMSO. Complex 5 exhibited remarkable PDT (photodynamic therapy) activity (IC₅₀ ≈ 0.02 μM) with a photocytotoxicity index (PI) value of >5000 in red light of 600-720 nm in A549 cancer cells. The biotin-conjugated complexes showed better photocytotoxicity in comparison to nonbiotinylated analogues in A549 cells. The complexes displayed less toxicity in HPL1D normal cells in comparison to A549 cancer cells. The emissive BODIPY complexes 3 and 5 (Φ_F ≈ 0.07 in DMSO) showed significant mitochondrial localization. Show less

This paper describes the synthesis of new 6-aminoflavone (6AFl (3)) and 6-aminochromone (6AC (4)) complexes with Cu(ii) and Ru(ii) ions ([Cu(6AC)₂Cl₂] (3a), [Cu(6AFl)₂Cl₂] (4a), [Ru(p-cymene)(6AC)Cl₂] (4b)) and comparison of their properties with the previously described 7-aminoflavone (7AFl (1)) and 7-amino-2-methylchromone (7A2MC (2)) analogues. The cytotoxic effect of all these complexes against two human leukaemia cell lines (HL-60 and NALM-6), melanoma WM-115 cells and COLO205 cells, is determined. The cytotoxicity of copper(ii) complexes, especially [Cu(6AFl)₂Cl₂] (3a) was higher than ruthenium(ii) complexes with the same ligands. Their cytotoxic potency was also stronger in comparison to the referential agents like cisplatin. The pro-oxidative properties were determined for the most active complexes and their ability to generate ROS (reactive oxygen species)/RNS (reactive nitrogen species) in cancer cells was confirmed. The type of ligand and the chemical structure of the tested complexes had an influence on the level of ROS/RNS generated in cancer cells. The redox properties of the copper complex compounds were evaluated by cyclic voltammetry, and compared with the data for Ru(ii) complexes. The reduction and oxidation processes of Ru(iii)/Ru(ii) and Cu(ii)/Cu(i) were described as quasi-reversible. Show less

Due to acquired resistance or limitations of the currently approved drugs against cancer, there is an urgent need for the development of new classes of compounds. Among others, there is an increasing attention towards the use of Ru(II) polypyridyl complexes. Most studies in the literature were made on complexes based on the coordination of N-donating bidentate ligands to the ruthenium core whereas studies on 2,2':6', 2″-terpyridine (terpy) coordinating ligands are relatively scare. However, several studies have shown that [Ru(terpy)2]²⁺ derivatives are able bind to DNA through various binding modes making these compounds potentially suitable as chemotherapeutic agents. Additionally, light irradiation of these compounds was shown to enable DNA cleavage, highlighting their potential use as photosensitizers (PSs) for photodynamic therapy (PDT). In this work, we present the systematic investigation of the potential of 7 complexes of the type [Ru(terpy)(terpy-X)]2+ (X = H (1), Cl (2), Br (3), OMe (4), COOH (5), COOMe (6), NMe2 (7)) as potential chemotherapeutic agents and PDT PSs. Importantly, six of the seven complexes were found to be stable in human plasma as well as photostable in acetonitrile upon continuous light irradiation (480 nm). The determination of the distribution coefficient logP values for the 7 complexes revealed their good water solubility. Complex 7 was found to be cytotoxic in the micromolar range in the dark as well as to have some phototoxicity upon light exposure at 480 nm in non-cancerous retinal pigment epithelium (RPE-1) and cancerous human cervical carcinoma (HeLa) cells. SYNOPSIS: The systematic investigation of the potential of 7 complexes of the type [Ru(terpy)(terpy-X)]²⁺ (terpy: 2,2':6', 2″-terpyridine; X = H (1), Cl (2), Br (3), OMe (4), COOH (5), COOMe (6), NMe2 (7)) as potential chemotherapeutic agents and photosensitizers for photodynamic therapy is presented. Show less

Two new complexes of Ru(II) with mixed ligands were prepared: [Ru(bpy)₂smp](PF₆) (1) and [Ru(phen)₂smp](PF₆) (2), in which smp = sulfamethoxypyridazine; bpy = 2,2'-bipyridine; phen = 1,10-phenanthroline. The complexes have been characterized by elemental and conductivity analyses; infrared, NMR, and electrospray ionization mass spectroscopies; and X-ray diffraction of single crystal. Structural analyses reveal a distorted octahedral geometry around Ru(II) that is bound to two bpy (in 1) or two phen (in 2) via their two heterocyclic nitrogens and to two nitrogen atoms from sulfamethoxypyridazine-one of the methoxypyridazine ring and the sulfonamidic nitrogen, which is deprotonated. Both complexes inhibit the growth of chronic myelogenous leukemia cells. The interaction of the complexes with bovine serum albumin and DNA is described. DNA footprinting using an oligonucleotide as substrate showed the complexes' preference for thymine base rich sites. It is worth notifying that the complexes interact with the Src homology SH3 domain of the Abl tyrosine kinase protein. Abl protein is involved in signal transduction and implicated in the development of chronic myelogenous leukemia. Nuclear magnetic resonance (NMR) studies of the interaction of complex 2 with the Abl-SH3 domain showed that the most affected residues were T79, G97, W99, and Y115. Show less

In this work, we aimed to understand the biological activity and the mechanism of action of three polymer-'ruthenium-cyclopentadienyl' conjugates (RuPMC) and a low molecular weight parental compound (Ru1) in cancer cells. Several biological assays were performed in ovarian (A2780) and breast (MCF7, MDA-MB-231) human cancer derived cell lines as well as in A2780cis, a cisplatin resistant cancer cell line. Our results show that all compounds have high activity towards cancer cells with low IC₅₀ values in the micromolar range. We observed that all Ru-PMC compounds are mainly found inside the cells, in contrast with the parental low molecular weight compound Ru1 that was mainly found at the membrane. All compounds induced mitochondrial alterations. PMC3 and Ru1 caused F-actin cytoskeleton morphology changes and reduced the clonogenic ability of the cells. The conjugate PMC3 induced apoptosis at low concentrations comparing to cisplatin and could overcame the platinum resistance of A2780cis cancer cells. A proteomic analysis showed that these compounds induce alterations in several cellular proteins which are related to the phenotypic disorders induced by them. Our results suggest that PMC3 is foreseen as a lead candidate to future studies and acting through a different mechanism of action than cisplatin. Here we established the potential of these Ru compounds as new metallodrugs for cancer chemotherapy. Show less

Organometallic Ru(II)-arene complexes have emerged as potential alternatives to platinum appended agents due to their wide range of interesting features such as stability in solution and solid, significant activity, less toxicity and hydrophobic property of arene moiety, etc. Hence, a series of Ru(II)-p-cymene complexes, [(η⁶-p-cymene)Ru(η²-N,N-L1)Cl]Cl (1), [(η⁶-p-cymene)Ru(η¹-N-L2)Cl₂] (2) and [(η⁶-p-cymene)Ru(η¹-N-L3)Cl₂] (3) were prepared from pyrazole based ligands [2-(1H-pyrazol-3-yl)pyridine (L1), 3-(furan-2-yl)-1H-pyrazole (L2) and 3-(thiophen-2-yl)-1H-pyrazole (L3)], and [RuCl₂-(η⁶-p-cymene)] dimer. The new Ru(II)-p-cymene complexes were well characterized by elemental analysis, and spectroscopic (FT-IR, UV-Visible, ¹H NMR, ¹³C NMR and mass) and crystallographic methods. The Ru(II)-p-cymene complexes (1-3) were found to adopt their characteristic piano stool geometry around Ru(II) ion. The calf thymus DNA (CT-DNA) binding ability of the new complexes was investigated by electronic absorption spectroscopic titration and viscosity methods. The molecular docking study results showed that complex 1 strongly bound with targeted biomolecules than 2 and 3. Docked poses of bidentate pyrazole based Ru(II)-p-cymene complex 1 revealed that the complex formed a crucial guanine N⁷ position hydrogen bond with DNA receptor. Complexes 1-3 might hydrolyze under physiological conditions and form aqua complexes 4-8, and docking calculations showed that the aqua complexes bound strongly with the receptors than original complexes. The in vitro cytotoxicity of the Ru(II)-p-cymene complexes and cisplatin was evaluated against triple negative breast cancer (TNBC) MDA-MB-231 cells. Our results showed that the inhibitory effect of bidentate pyrazole based Ru(II)-p-cymene complex 1 on the growth of breast cancer cells was superior to other tested complexes. Show less

A novel ligand BOPIP (BOPIP = {2-(4-(benzyloxy)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline}) and its mononuclear Ru(II) polypyridyl complexes [Ru(phen)₂ BOPIP]²⁺(1) (phen = 1,10-Phenanthrolene), [Ru(bpy)₂ BOPIP]²⁺(2) (bpy = 2,2' bipyridyl), [Ru(dmb)₂ BOPIP]²⁺(3) (dmb = 4, 4' -dimethyl 2, 2' -bipyridine), [Ru(Hdpa)₂ BOPIP]²⁺(4) (Hdpa = 2,2'dipyridylamine) have been synthesized successfully and characterized by elemental analysis, UV-vis, IR, ¹H, ¹³ C-NMR, and ESI-MS Spectroscopy. The interaction of these complexes with CT-DNA was studied using absorption, emission techniques, viscosity measurements and molecular docking studies. The docking study also supports the binding ability of complexes obtained through the absorption and emission techniques. These studies reveal that the Four Ru(II) polypyridyl complexes bind to DNA predominantly by intercalation. The Antimicrobial activity and cytotoxicity of these complexes are also reported. Show less

An organoiridium-albumin bioconjugate (Ir1-HSA) was synthesized by reaction of a pendant maleimide ligand with human serum albumin. The phosphorescence of Ir1-HSA was enhanced significantly compared to parent complex Ir1. The long phosphorescence lifetime and high ¹ O₂ quantum yield of Ir1-HSA are highly favorable properties for photodynamic therapy. Ir1-HSA mainly accumulated in the nucleus of living cancer cells and showed remarkable photocytotoxicity against a range of cancer cell lines and tumor spheroids (light IC₅₀ ; 0.8-5 μm, photo-cytotoxicity index PI=40-60), while remaining non-toxic to normal cells and normal cell spheroids, even after photo-irradiation. This nucleus-targeting organoiridium-albumin is a strong candidate photosensitizer for anticancer photodynamic therapy. Show less

Rhodium(III) anticancer drugs can exert preferential antimetastatic or cytotoxic activities, which are dependent on subtle structural changes. In order to delineate factors affecting the biotransformations and speciation, mer,cis-[RhCl₃( S-dmso)₂( O-dmso)] (A1) and mer,cis-[RhCl₃( S-dmso)₂(²N-indazole)] (A2) have been studied by X-ray absorption spectroscopy (XAS). Interactions of these complexes with saline buffer, cell culture media, serum proteins (albumin and apo-transferrin), native and chemically degraded collagen gels, and A549 cells have been studied using linear combination fitting (LCF) and 3D scatter plots of XAS data. Following initial aquation and hydrolysis reactions involving stepwise displacement of Cl^- and S-/ O-dmso ligands, the Rh(III) complexes underwent further ligand substitution reactions with biological nucleophiles (e.g., amino acid residues of serum proteins). The reaction of A1 with chemically degraded collagen gel was postulated to be a key reason for its antimetastatic activity. Analyses of the XAS of Rh-treated bulk cells were consistent with structure-reactivity relationships in which the more reactive A1 was predominantly antimetastatic and the less reactive A2 was predominantly cytotoxic, showing relationships parallel to typical Ru(III) anticancer agents, i.e., NAMI-A ([ImH] trans-[RuCl₄( S-dmso)( N-imidazole)₂], ImH = imidazolium cation) and KP1019/NKP1339 (KP1019, [IndH] trans-[RuCl₄(N-indazole)₂], IndH = indazolium cation; NKP1339, sodium trans-[RuCl₄(²N-indazole)₂]), respectively. Show less

TFIIH is a 10-subunit complex involved in transcription and DNA repair. It contains several enzymatic activities including a ATP-dependent DNA translocase in XPB and a cyclin-dependent kinase in CDK7. Recently the discovery of several XPB and CDK7 inhibitors with specific impact on the transcriptional addiction of many tumors pinpointed these activities as potential target in cancer chemotherapy. Unexpectedly a basal transcription factor involved in global mRNA expression now emerges a one of the most clinically promising Achilles heels of cancerous cells. These inhibitors also proved to be useful tools to unveil new functions of TFIIH in gene expression. Show less

With the aim of enhancing the biological activity of ruthenium-nitrosyl complexes, new compounds with four equatorially bound indazole ligands, namely, trans-[RuCl(Hind)₄(NO)]Cl₂·H₂O ([3]Cl₂·H₂O) and trans-[RuOH(Hind)₄(NO)]Cl₂·H₂O ([4]Cl₂·H₂O), have been prepared from trans-[Ru(NO₂)₂(Hind)₄] ([2]). When the pH-dependent solution behavior of [3]Cl₂·H₂O and [4]Cl₂·H₂O was studied, two new complexes with two deprotonated indazole ligands were isolated, namely [RuCl(ind)₂(Hind)₂(NO)] ([5]) and [RuOH(ind)₂(Hind)₂(NO)] ([6]). All prepared compounds were comprehensively characterized by spectroscopic (IR, UV-vis, ¹H NMR) techniques. Compound [2], as well as [3]Cl₂·2(CH₃)₂CO, [4]Cl₂·2(CH₃)₂CO, and [5]·0.8CH₂Cl₂, the latter three obtained by recrystallization of the first isolated compounds (hydrates or anhydrous species) from acetone and dichloromethane, respectively, were studied by X-ray diffraction methods. The photoinduced release of NO in [3]Cl₂ and [4]Cl₂ was investigated by cyclic voltammetry and resulting paramagnetic NO species were detected by EPR spectroscopy. The quantum yields of NO release were calculated and found to be low (3-6%), which could be explained by NO dissociation and recombination dynamics, assessed by femtosecond pump-probe spectroscopy. The geometry and electronic parameters of Ru species formed upon NO release were identified by DFT calculations. The complexes [3]Cl₂ and [4]Cl₂ showed considerable antiproliferative activity in human cancer cell lines with IC₅₀ values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru-NO complexes [3]Cl₂ and [4]Cl₂ was studied and p53-independent mode of action was confirmed. The effects of NO release on the cytotoxicity of the complexes with or without light irradiation were investigated using NO scavenger carboxy-PTIO. Show less

New ruthenium methyl-cyclopentadienyl compounds bearing bipyridine derivatives with the general formula [Ru(η⁵-MeCp)(PPh₃)(4,4'-R-2,2'-bpy)]⁺ (Ru1, R = H; Ru2, R = CH₃; and Ru3, R = CH₂OH) have been synthesized and characterized by spectroscopic and analytical techniques. Ru1 crystallized in the monoclinic P2₁/ c, Ru2 in the triclinic P1̅, and Ru3 in the monoclinic P2₁/ n space group. In all molecular structures, the ruthenium center adopts a "piano stool" distribution. Density functional theory calculations were performed for all complexes, and the results support spectroscopic data. Ru1 and Ru3 were poor substrates of the main multidrug resistance human pumps, ABCB1, ABCG2, ABCC1, and ABCC2, while Ru2 displayed inhibitory properties of ABCC1 and ABCC2 pumps. Importantly, all compounds displayed a very high cytotoxic profile for ovarian cancer cells (sensitive and resistant) that was much more pronounced than that observed with cisplatin, making them very promising anticancer agents. Show less

In this study, we synthesized a novel metal flavonoid complex and investigated its effects on the non-small cell lung cancer cell lines, A549 and toxicity on the human dermal fibroblast cell lines, HDFa. ¹H, ¹³C NMR, single crystal X-ray diffraction and elemental micro analysis (C,H,N,S/O) were used to characterize the synthesized kaempferol-based Ru (II) complex. Cell toxicity was studied using MTT assay and electric cell substrate impedance sensing (ECIS). It was evident from the MTT results that no significant cytotoxicity in HDFa cells occurs with the synthesized complex, but in case of A549 cells, significant cytotoxicity was observed even at low concentrations (10-20 μm). In addition, the effect of the newly synthesized complex on the A549 cell line was studied by investigating the cellular damage via atomic force microscopy and DNA fragmentation assay. The obtained results revealed that the synthesized complex was able to inhibit the cancer cells and have shown moderate anticancer activity against A549 cancer cell lines. In addition, it was evident that the complex was more active than kaempferol and well tolerated by normal cell lines. Show less

Although different types of metal-based anticancer complexes have been synthesized, novel complexes to reduce the serious side effect of cisplatin and conquer cancer metastasis are still highly desired. Here, we report the synthesis, characterization, and biological activity of a novel heterodinuclear Pt(IV)-Ru(II) anticancer prodrug. The Pt(IV)-Ru(II) complex exhibits good stability in both water and PBS solution. Biological evaluation revealed that this bifunctional Pt(IV)-Ru(II) complex utilizes the advantages of two metal centers to have both cytotoxicity and antimetastatic property as designed. Although the complex has comparable cytotoxicities to cisplatin in tested cancer cell lines, this prodrug selectively kills cancer but not normal cells, and the IC₅₀ values of the Pt(IV)-Ru(II) complex are 7-10 times higher than those of cisplatin toward normal cells. The cancer cell selectivity is further demonstrated by a cancer-normal cell coculture system. In addition, the antimetastatic properties of the heterodinuclear complex are assessed by using highly metastatic human breast cancer cells, and the results show that the migration and invasion of cancer cells are effectively restrained after the treatment. Moreover, the Pt(IV)-Ru(II) complex displays lower toxicity than cisplatin in developing zebrafish embryos. We, therefore, report an example of heterodinuclear Pt(IV)-Ru(II) complex not only to defeat both drug resistance and cancer metastasis but also having significantly improved cancer cell selectivity and reduced in vivo toxicity than cisplatin. Show less

Ruthenium(II/III) metal complexes have been widely recognized as the alternative chemotherapeutic agents to overcome the drug resistance and tumor recurrence associated with platinum derivatives. In this work, a novel ruthenium(II) triazine complex namely, 1 ([Ru(bdpta)(tpy)]²⁺) was synthesized and spectroscopically characterized. Drug resistant cancer stem cells (CSCs) were used to evaluate the cytotoxicity of Ru(II) complex 1. The complex 1 showed a greater cytotoxic potential with IC₅₀ values lower than that of cisplatin. The intracellular localization assay confirmed that the complex 1 was effectively distributed into mitochondria as well as endoplasmic reticulum (ER), and executed a ROS-mediated calcium and Bax/Bak dependent intrinsic apoptosis. Interestingly, direct interaction between complex 1 and glucose regulated protein 78 (GRP78), a protein associated with drug resistance caused the ROS-mediated ubiquitination of GRP78. Notably, western blot and confocal microscopy analysis confirmed that complex 1 significantly reduced the protein levels of GRP78. Dose-dependent in vivo antitumor efficacy against CD133+HCT-116 CSCs derived tumor xenograft further validated that complex 1 could be an effective chemotherapeutic agent. Show less

Fluorescent 4-ethylthio-1,8-naphthalimides containing rhodium(I) N-heterocyclic carbene (NHC) and ruthenium (II) NHC fragments were synthesised and evaluated for their antiproliferative effects, cellular uptake and DNA-binding activity. Both types of organometallics triggered ligand dependent efficient cytotoxic effects against tumor cells with the rhodium(I) NHC derivatives causing stronger effects than the ruthenium (II) NHC analogues. Antiproliferative effects could also be observed against several pathogenic Gram-positive bacterial strains, whereas the growth of Gram-negative bacteria was not substantially affected. Cellular uptake was confirmed by atomic absorption spectroscopy as well as by fluorescence microscopy indicating a general ligand dependent accumulation in the cells. An in-depth study on the interaction with DNA confirmed insertion of the naphthalimide moiety between the planar bases of B-DNA via an intercalation mechanism, as well as its stacking on top of the quartets of G-quadruplex structures. Furthermore, additional coordinative binding of the organometallic complexes to the model DNA base 9-ethylguanine could be detected. The studied compounds thus represent promising bioorganometallics featuring strong pharmacological effects in combination with excellent cellular imaging properties. Show less

In the present study, the potential anti-neoplastic properties of a series of ruthenium half-sandwich complexes of formula [Ru(η⁶-arene)Cl₂(PR¹R²(1-pyrenyl))] (η⁶-arene = p-cymene and R¹ = R² = methyl for 1; η⁶-arene = methylbenzoate and R¹ = R² = methyl for 2; η⁶-arene = p-cymene and R¹ = R² = phenyl for 3; η⁶-arene = methylbenzoate and R¹ = R² = phenyl for 4; η⁶-arene = p-cymene, R¹ = methyl and R² = phenyl for 5; η⁶-arene = methylbenzoate, R¹ = methyl and R² = phenyl for 6) have been investigated. The six structurally related organoruthenium(II) compounds have been prepared in good yields and fully characterized; the X-ray structures of three of them, i.e., 1, 2, and 4, were determined. Although the piano-stool compounds contain a large polycyclic aromatic moiety, viz. a 1-pyrenyl group, they do not appear to interact with DNA. However, all the piano-stool complexes show significant cytotoxic properties against five human cell lines, namely, lung adenocarcinoma (A549), melanoma (A375), colorectal adenocarcinoma (SW620), breast adenocarcinoma (MCF7), and nontumorigenic epithelial breast (MCF10A), with IC₅₀ values in the micromolar range for most of them. In addition, the most active compound, i.e., 2, induces a remarkable decrease of cell viability, that is in the nanomolar range, against two human neuroblastoma cell lines, namely, SK-N-BE(2) and CHLA-90. Complexes 1-6 are all capable of inducing apoptosis, but with various degrees of magnitude. Whereas 1, 3, 5, and 6 have no effect on the cell cycle of A375 cells, 2 and 4 can arrest it at the G₂/M phase; furthermore, 2 (which is the most efficient compound of the series) also stops the cycle at the S phase, behaving as the well-known anticancer agent cisplatin. Finally, 2 is able to inhibit/reduce the cell migration of neuroblastoma SK-N-BE(2) cells. Show less

There is an urgent need to discover new, selective compounds to add to the limited arsenal of chemotherapeutics displaying selective toxicity for aggressive triple-negative breast cancer (TNBC) cells. The effect of two, recently developed metal-based half-sandwich complexes [Os(η6-pcym)(bphen)(dca)]PF6 (Os-dca) and [Ru(η6-pcym)(bphen)(dca)]PF6 (Ru-dca) [pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene); bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline); dca = dichloroacetate] on triple-negative breast cancer cells MDA-MB-231 is reported. The complexes display selective toxicity in several tumor cells (at submicromolar concentrations), and a prominent effect is observed against highly progressive triple negative breast cancer MDA-MB-231 cells for Os-dca. The lower potency of Ru-dca in comparison with Os-dca is apparently connected with a relatively quick release of the dca ligand due to the hydrolysis of Ru-dca before this complex enters the cells. Remarkably, both Os-dca and Ru-dca reduce successfully metastasis-related properties of the triple-negative breast cancer cells such as migration, invasion, and re-adhesion. The anti-metastatic effects of Os-dca and Ru-dca are associated with their ability to suppress matrix metalloproteinase activity and/or production and reduce the expression of aquaporins. Further detailed mechanistic studies reveal that Os-dca reverses Warburg's effect and oncosis seems to be a prominent mode of cell death that predominates over apoptosis. As such, Os-dca can efficiently overcome the resistance of cancer cells to clinically-used apoptotic inducers cisplatin and carboplatin. The cytostatic and anti-metastatic properties of Os-dca in MDA-MB-231 provide a strong impetus for the development of new metal-based compounds to target hardly treatable human TNBC cells and displaying different modes of action compared to the antitumor metallodrugs in clinical use. Show less

Two new ruthenium complexes, [Ru(η⁵-Cp)(PPh₃)(2,2'-bipy-4,4'-R)]⁺ with R = -CH₂OH (Ru1) or dibiotin ester (Ru2) were synthesized and fully characterized. Both compounds were tested against two types of breast cancer cells (MCF7 and MDA-MB-231), showing better cytotoxicity than cisplatin in the same experimental conditions. Since multidrug resistance (MDR) is one of the main problems in cancer chemotherapy, we have assessed the potential of these compounds to overcome resistance to treatments. Ru2 showed exceptional selectivity as P-gp inhibitor, while Ru1 is possibly a substrate. In vivo studies in zebrafish showed that Ru2 is well tolerated up to 1.17 mg/L, presenting a LC₅₀ of 5.73 mg/L at 5 days post fertilization. Show less

A mutifunctional ruthenium-based conjugate Ru-BSe was designed and synthesized. The Ru complex with favorable bioimaging function was covalently linked with a cancer-targeted molecule that could be effectively internalized by the tumor to realize enhanced theranostic effects. The pH-response of the Ru conjugate in tumor acidic microenvironment causes ligand substitution and release of therapeutic complex. This activated complex remains inert to the reducing biomolecule-glutathione and terminally locates in mitochondria, in which it triggers oxidative stress, and activates intrinsic apoptosis. Real-time monitoring reveals that this Ru conjugate could selectively accumulate in tumor tissue in vivo, which significantly suppresses tumor progression and alleviate the damage to normal organs, realizing the precise cancer theranosis. Show less

Six novel polypyridyl ruthenium complexes with (E)-2-styryl-1H- imidazo[4,5-f][1,10]phenanthroline ligand and its analogues have been designed to enhance the DNA intercalation ability of their model compound [Ru(bpy)₂(pip)]²⁺ (bpy = 2,2'-bipyridine, pip = 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline). As shown in the optimized geometry of the complexes, the introduction of styryl group not only extended the conjugated area of the intercalative ligand, but also retained the excellent planarity. These two merits have been proven to be beneficial for their DNA intercalation, thus greatly improved their inhibition activity towards DNA transcription by RNA polymerase and DNA topoisomerase, two enzymes closely related to both DNA and tumor cell growth. The relationships between the substituent group structures and the biological activities have also been investigated from energetic and electronic aspects by quantum chemistry calculations. Results from cell cytotoxicity and apoptosis assay testified that the styryl substituted ruthenium complexes possessed higher antitumor activity than [Ru(bpy)₂(pip)]²⁺, as expected. As quantified in the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, the tumor cell death is caused mostly through apoptosis for Ru2 and Ru3, while non-apoptotic processes for Ru1, Ru4 and Ru5. In vitro fluorescence evaluation revealed that all complexes located mainly in cytoplasm, but the three complexes with high antiproliferative activity could enter nucleus. All complexes have shown apparent lower cytotoxicity towards normal human colon epithelial cell CCD-841-CON than the examined tumor cell lines. Show less